Among known streptogramins, pristinamycin (RP 7293), an antibacterial of natural origin produced by Streptomyces pristinaespiralis, was isolated for the first time in 1955. Pristinamycin marketed under the name Pyostacine.RTM. consists mainly of pristinamycin IA and pristinamycin IIA.
Another antibacterial of the streptogramin class, namely virginiamycin, has been prepared from Streptomyces virginiae, ATCC 13161 [Antibiotics and Chemotherapy, 5, 632 (1955]. Virginiamycin (Staphylomycine.RTM.) consists mainly of factor S and factor M.sub.1.
In U.S. Pat. No. 3,325,359, pharmaceutical compositions comprising antibiotic substances constituting antibiotic 899, namely factor S and factor M.sub.1, have been described.
In Patent Application FR 2,619,008, the use of group A and group B components for the treatment of ache has been described.
The antibacterials of natural origin of the streptogramin class consist of a mixture of 2 groups of components: group B components and group A components, each group having an antibacterial activity of its own. It has been demonstrated that the combination made up of the 2 groups of components produces a synergy of action which results in an enhanced bacteriostatic and bactericidal activity and in a broadening of the spectrum of activity.
In Streptogramine als Modelsysteme fur den Kationentransport durch Membranen, Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Facultat der Georg-August Universitat zu Gottingen, Gottingen 1979, in Antibiotics III, 521 (1975) and in Antibiotics of the virginiamycin family, Inhibitors which contain synergistic components, C. Cocito, Microbiological Reviews, 145-98 (1979), groups A and B components of streptogramins have been described. J. Preud'Homme, P. Tarridec and A. Belloc, Bull. Soc. Chim. Fr., 2, 585 (1968) have also described natural pristinamycin as well as the different components of which it is made up.
All attempts to make purified combinations of streptogramins invariably involve the group A majority component [pristinamycin IIA (PIIA)] which is considered to be responsible for the activity and for the synergy of action. The conclusion from some studies has pointed, moreover, to the importance of this component, which produces better synergy: EP 506,561 (page 2).
However, these attempts have never been crowned with success, on the one hand because of the difficulties of industrial preparation, and most of all because purified pristinamycin IIA is a crystallide product whose bioavailability has proved to be too low for it to be possible to envisage making it the active principle of a medicinal product.
From the standpoint of the industrial preparation of such products, the techniques available had not hitherto made it possible to obtain, on a preparative scale, a sufficiently purified form and the production of batches of sufficiently constant and reproducible quality to satisfy the requirements of the laws of some countries concerning registration.
As an example, industrial batches of natural pristinamycin contain, after purification, an amount of impurities which can reach 20%. The attempts at purification carried out hitherto have invariably ended in failure and very often in degradation of one of the groups of components, because these are labile products for which many operations lead to opening of the ring structure or to dehydration of the group A components. As a result, for many years it was considered that an improvement in the degree of purity could not be achieved. In 1988, purification was still considered to be a problem: J. of Liq. Chromatography, 11 (11), 2367 (1988). Also in 1988, N. K. SHARMA and M. J. O. ANTEUNIS likewise declared that separation and purification of the components of virginiamycin were possible for analytical purposes, but could not be envisaged for the production of the products in view of the difficulties encountered: Bull. Soc. Chim. Belg., 97 (3) 193 (1988).
In consequence of this situation, the marketing of pristinamycin (Pyostacine.RTM.) was irrevocably limited to certain countries such as France and Belgium. The same applied to virginiamycin (Staphylomycine.RTM.), marketed only in a limited number of countries in relation to human medicine, as well as to mikamycin whose marketing (limited to Japan) has now been stopped. This has hence resulted in some populations being deprived of the treatment in the case of severe infections caused by Gram-positive cocci (in particular infections caused by methicillin-resistant staphylococci), or of the treatment in the case of sexually transmitted diseases.
In the field of antibacterials, it is well known by practitioners that allergies or resistances may develop after administration of some classes of antibiotics [The New England Journal of Medicine, 324 (9), 601 (1991)]. In the hospital environment, many resistant strains of Staphylococcus aureus are known in particular. For this reason, it is extremely useful for the doctor to have at his disposal a wide range of chemically different classes so as to be able to match the treatment to the particular case of the patient to be treated. The consequence of the failure of a particular class to be marketed can be very serious, or even dramatic, since it can result in patients who do not tolerate the other classes of antibiotic being deprived of treatment.
Thus, the attempts made at purification had always been directed towards removing the minority components of streptogramins, these being regarded as non-essential and, for the most part, as impurities.
Among the group A components of natural streptogramins, pristinamycin IIB (PIIB) is a minority component whose proportion by weight is less than 10% in natural pristinamycin, and most often of the order of 8% or even of the order of 6% in virginiamycin.